The hydroxylated adamantane is known as a monomer of a functional resin such as a photosensitive resin and the like in the photolithography field (Patent Document 1), or an inhibitor of 11beta-hydroxysteroid dehydrogenase type I (11βHSD1) in the field of medicines (Patent Document 2, page 27). In addition, a compound having an adamantyl group is known also as a DPPIV inhibitor. And, when these compounds are synthesized, a compound wherein a part of substituents of the hydroxylated adamantane is protected is useful as a synthesis intermediate from its reactivity.
A process for producing a hydroxylated adamantane derivative using a microorganism has been previously known. For example, a hydroxylated adamantane derivative protected with benzamide can be produced using in vivo conversion of Beauveria sulfurescens (Non-patent Document 1). In addition, regarding an adamantane derivative protected with phthalimide, it has been reported that a dihydroxy form can be produced by in vivo conversion of Sporotrichum sulfurescens (Non-patent Document 2).
Cytochrome P450 (hereinafter, also referred to as P450) is a generic name of protoheme-containing proteins exhibiting a specific absorption band (Soret band) at around 450 nm when it is reduced and carbon monoxide is bound thereto. P450 is bound to a microsome of many animal and plant tissues, fungi, and yeasts, or an internal membrane of mitochondria of a part of animal tissues. Additionally, it exists in a soluble form in certain bacteria or fungi.
P450 has various substrate specificities, and there are enzymes exhibiting very broad substrate specificity, which can utilize a variety of organic compounds as a substrate. On the other hand, there are enzymes having more restricted substrate specificity, which react only with relatively limited kinds of organic compounds. P450 is involved in biosynthesis of bioactive lipids such as cholesterol, steroid hormone, bile acid and active-type vitamin D, metabolism of bioactive lipids such as heme, fatty acid and eicosanoid, metabolism of exogenous chemical substances including drugs, and the like. As specific function of P450, it is known that P450 catalyzes a variety of reactions such as a hydroxylation reaction, an epoxidation reaction, a dealkylation reaction, a denitrification reaction and the like of xenobiotic in cells expressing the P450.
Some P450s derived from microorganisms such as fungi or bacteria are known that they serve for production of industrially useful substances, and a part thereof are actually utilized in industrial production of useful drugs. A representative example is to hydroxylate a 6β-position of compactin with an actinomycete, Streptomyces carbophilus, and obtain pravastatin which is an antihyperlipemic agent, as a product (Non-patent Document 3, Patent Document 3). A process for producing active-type vitamin D3 by hydroxylating a 1α-position and a 25-position of vitamin D3 utilizing an actinomycete, Pseudonocaria autotrophica has been also put into practical use.
With respect to hydroxylation of adamantane, Non-patent Document 4 describes that adamantane is hydroxylated with P450cam, which is P450 of Pseudomonas putida. In addition, Non-patent Document 5 describes that five microorganisms hydroxylating adamantane were screened from 470 microorganisms, and suggests that P450 is involved in hydroxylation of adamantane in Streptomyces griseoplanus, which is one of those microorganisms.
However, none of documents describe or suggest hydroxylation of a compound having an adamantane skeleton using P450, for example, hydroxylation of an N-(2-adamantyl)-benzamide derivative using P450.    [Patent Document 1] Japanese Patent Application Laid-Open (JP-A) No. 2006-63061    [Patent Document 2] WO04/056744    [Patent Document 3] JP-A No. 6-70780    [Non-patent Document 1] Journal of Organic Chemistry, 1992, vol. 57, p. 7209-7212    [Non-patent Document 2] The Journal of Organic Chemistry, 1968, vol. 33, p. 3201-3207    [Non-patent Document 3] Gene, 1995, vol. 163, p. 81-85    [Non-patent Document 4] Archives of Biochemistry and Biophysics, 1984, vol. 228, p. 493-502    [Non-patent Document 5] Applied Microbiology and Biotechnology, 2006, vo. 71, p. 502-504